1. Field of Invention
This invention relates to substituted dibenz[b,f] [1,4] oxazepin-11(10H)-ones useful for the reversal of multidrug resistance of cancer cells to multiple cytotoxic drugs. Thus the compounds of the instant invention can be used for adjuvant chemotherapy for neoplasias resistant to multiple drugs.
2. Background of Related Art
The treatment of human tumors with cytotoxic drugs is an important part of the modern clinical cancer therapy. A major obstacle to effective cancer chemotherapy is the resistance of tumor cells to antineoplastic agents. Drug resistance in human malignancies may arise from multiple mechanisms. Of particular importance is the cross resistance of cancer cells to a diverse group of lipophilic drugs with unrelated structures and functions, a phenomenon known as multidrug resistance (MDR).
A common feature detected in all MDR cells in early studies was the reduction in intracellular steady state drug accumulation relative to sensitive cells. Later, it was discovered that this phenotype was frequently associated with the increased expression of a plasma membrane glycoprotein (P-gp) of 170kDa. The implication of this protein in MDR was confirmed by its ability to confer drug resistance through transfection of cloned P-gp gene (MDR-1) into sensitive cells. See: Grace Bradley, Peter F. Juranka & Victor Ling--Mechanisms of multidrug resistance, Bioch. Biophys. Acta,948, pp 87-128 (1988); Jane A. Endicott & Victor Ling - The biochemistry of P-glycoprotein-mediated multidrug resistance, Ann. Rev. Biochem, 58, pp 137-171 (1989); James M. Ford & William N. Hait--Pharmacology of drugs that alter multidrug resistance in cancer, Pharmacological Reviews. 42 , pp 155-199 (1990).
P-gp consists of two symmetrical halves, each has an ATP binding domain. Evidence suggests that it functions as an energy dependent pump with a broad range of substrate specificity. Relatively high levels of P-gp have also been found in certain normal human tissues, such as adrenal glands, kidney, colon and placenta. However, its physiological role and its natural substrate are as yet unclear. P-gp may serve to export naturally occurring toxins or xenobiotics as a detoxification mechanism. Surveys of clinical samples have found increased levels of P-gp in tumors derived from tissues which normally overexpress MDR-1 message. In addition, apparently, there is a direct correlation between the expression of P-gp with some drug refractory hematological malignancies and childhood soft tissue sarcomas, which do not normally express P-gp. See: Mace Rothenberg & Victor Ling--Multidrug Resistance: Molecular Biology and Clinical Relevance, J. Nat. Cancer Inst., 81, pp 907-910, (1989); Helen S. L. Chan, Paul S. Thorner, George Haddad and Victor Ling--Immunohistochemical Detection of P-glycoprotein: Prognostic Correlation in Soft Tissue Sarcoma of Childhood, J. Clin. Oncol., 8, pp 689-704 (1990). These findings support potential clinical role played by P-gp in both intrinsic and acquired MDR which ultimately render some cancer treatments inefficacious.
Several strategies have been devised to circumvent clinical MDR. One promising approach is the utilization of chemosensitizing agents which can inhibit active efflux of drugs in resistant cells. Numerous compounds including calcium antagonists, calmodulin inhibitors, and some drug analogues have shown variable abilities to reverse MDR. Most of these agents are lipophilic and may act as a substrate for the P-gp, thereby competitively inhibiting its drug efflux effect. Excellent reviews have recently been published on agents that alter multidrug resistance in cancer. See: James M. Ford & William N. Hait--Pharmacology of Drugs that Alter Multidrug Resistance in Cancer, Pharmacological Reviews, 42, pp 155-199 (1990); David J. Stewart & William K. Evans--Non-chemotherapeutic Agents that Potentiate Chemotherapy Efficacy, Cancer Treatment Reviews, 16, pp 1-40 (1989).
The major limiting factor to use certain MDR reversing agents in cancer patients so far is their toxicity which prevents them from reaching effective concentrations during treatment. Thus, challenge remains in the search of ideal MDR reversing agents which are more potent but less toxic and pharmacologically acceptable for clinical applications.
We have recently found a group of substituted dibenz[b,f][1,4]oxazepin-11(10H)-ones (hereinafter often abbreviated simply as oxapezines) with potent MDR reversing abilities. Oxazepines with structures somewhat related to those of the instant invention can be found, for example, in U.K. Patent No. 1,164,579 published Sept. 17, 1969, which discloses oxazepines of formula II ##STR3## wherein R.sup.8 is hydrogen or halogen, R.sup.7 is hydrogen or C.sub.1-6 alkyl, and one of R.sup.9 and R.sup.10 represents a free amino group whilst the other represents a hydrogen atom. Oxazepines of the formula II are reported to have analgesic, antipyretic, and sedative properties. Furthermore, Nagarajan et al. in the Indian Journal of Experimental Biology, 12, pp 217-224, at p 229, (1974), disclose oxazepine of formula III. Compound of formula III was made by the intramolecular cyclization of compound of formula IV in hot DMF. ##STR4## Analogous methods have been employed to make oxazepines of formula II above.
Neither oxazepines of formula II or III have been identified to have MDR reversing activities.